Clinical definition higher cortical functions

Transcription

1 ALZHEIMER S DISEASE

2 Clinical definition 1. Dementia is a chronic progressive, degenerative, cerebral disorder; 2. It affects higher cortical functions including memory, thinking and orientation; 3. Alzheimer s disease (AD) is the most common form of dementia. 4. AD owns characteristic neuropathological and neurochemical features.

3 Clinical definition 1. People with Alzheimer s disease lose the ability to carry out routine daily activities like dressing, toileting, travelling and handling money; 2. Behavioural changes such as aggression are particularly disturbing for carers.

4 Natural history of Alzheimer's disease Onset Progression Duration gradual, probably imperceptible slow and gradual, but not linear; progressive amnesia most common less than 10 years, on average, from diagnosis to death Cognitive function Alzheimer s disease Vascular dementia Dementia with Lewy bodies Time

5 Neuropathology of Alzheimer s Disease Cell loss, senile plaques, and neurofibrillary tangles appear regularly in the neocortex, hippocampus, amygdala, and basal nucleus of Meynert.

6 Neuropathology of Alzheimer s Disease After the importance of the hippocampus and the cholinergic system for memory and learning had been emphasized (Drachman and Ommaya, 1964), the selective loss of cholinergic neurons and their enzyme activities in Alzheimer brain were reported (Davies and Maloney, 1976), associated with disorders of cortical cholinergic innervation (Coyle et al., 1983).

7 Neuropathology of Alzheimer s Disease It is well known that the first component of the disease cascade is the production of amyloid. Amyloid produces inflammation around the senile plaques, and the inflammation sets up a cascade of seemingly uncontrollable changes.

8 Available treatments At present, no treatment can prevent or cure Alzheimer s disease

9 Available treatments The 5 drugs approved for the treatment of Alzheimer s disease are tacrine, donepezil, galantamine and rivastigmine all of which are cholinesterase inhibitors and memantine which works through the glutamate system.

10 Current treatments for Alzheimer s Disease: Cholinesterase Inhibitors Acetylcholinesterase is a key inactivator of neuronally released acetylcholine. It is commonly understood that the inhibition of the enzyme acetylcholinesterase can boost the action of acetylcholine long enough to enhance cognition in patients suffering from Alzheimer s disease.

11 Cholinergic hypothesis Cholinergic neurons are essential for memory scopolamine inhibition of cholinergic function results in cognitive loss lesion in cholinergic tracts also results in cognitive loss cholinergic-rich grafts restore memory functioning Cholinergic neurons are lost first and most in AD choline acetyltransferase (ChaT) markers lost in AD reduced choline uptake and ACh release in AD neuronal loss in cholinergic nuclei in AD Blokland (1995); Dunnett (1991); Francis et al (1999)

12 Available treatments AChE-I Donepezil inhibits acetylcholinesterase Rivastigmine inhibits both acetylcholinesterase and butyrylcholinesterase Galantamine inhibits acetylcholinesterase while allosterically modulating nicotinic cholinergic receptors.

13 Cognition: compounds compared Compound Dose Duration ADAS-cog (mg/day) (months) (treatment placebo difference) Tacrine Donepezil Rivastigmine Galantamine

14 Tacrine First AChEI to be approved for use in AD Four times a day dosing Most beneficial effects at high dosage Effects on cognition seen within weeks Severely limited by liver enzyme elevation in 1/3 of patients Also has muscarinic and nicotinic receptor-binding properties? Might be disease-modifying? Might show an APOE-selective response

15 Donepezil Reversible acetylcholinesterase (AChE) inhibitor Half life < 70 hours Once-daily dosing Two doses: 5 mg/day and 10 mg/day Greater efficacy at 10 mg/day Subjected to Cochrane review Evidence for improvement in cognition, global state and possibly function Side-effects similar to other AChEIs nausea and vomiting most common Side-effects often mild and attenuate with time Nightmares may occur

16 Rivastigmine Pseudo-irreversible acetylcholinesterase (AChE) inhibitor Half life ~2 hours / effects on AChE ~10 hours Twice-daily dosing Dose-titration regimen Greater efficacy (and more side-effects) at higher doses Evidence for improvements in cognition, global state and possibly function Evidence for benefits in those with vascular risk factors Side-effects similar to other AChEIs nausea and vomiting most common Few interactions with other drugs Pharmacoeconomic modelling suggests modest cost savings

17 Galantamine Competitive reversible acetylcholinesterase (AChE) inhibitor Allosteric modulator of nicotinic receptors Half life ~2 hours / effects on AChE ~10 hours Slow dose-titration reduces side-effects Evidence for improvement in cognition, global state and possibly function No effect of APOE Benefit maintained to 12 months Side-effects similar to other AchEIs nausea and vomiting most common

18 Available treatments There are limitations to these medications, however,there is typically only a modest improvement from baseline. Additionally, the effects are not sustained indefinitely, and the disease continues to progress even while patients are receiving treatment with cholinesterase inhibitors.

19 Available treatments Adverse events are manageable, and with careful titration, patients can tolerate increases quite well; however, side effects can include diarrhea, neausea, vomiting, dyspepsia, asthenia, dizziness, headache, weight loss, and even anorexia sometimes to such extreme that patients must discontinue treatment.

20 Glutamatergic hypothesis of dementia Glutamate is the main fast excitatory transmitter in regions associated with cognition and memory Cortical and subcortical structures that contain glutamatergic receptors are structurally damaged in AD Glutamate acts as an excitotoxin, causing neuronal death when chronically released Animal data suggest that NMDA-receptor antagonists provide neuroprotection Clinical signs of dementia correlate with deficits of glutamatergic association fibres

21 Mechanism of action of memantine (1) Memantine allows the physiological activation of the NMDA-receptor Memantine does not leave the NMDAreceptor channel following tonic low level activation of NMDA-receptors

22 Antipsychotics as a therapeutic tool Have been used to treat behavioural disturbance sleeplessness psychosis aggression the nursing home Good practice suggests define the target symptom choose the antipsychotic carefully with respect to side-effect profile start low, go slow assess response withdraw medication as soon as possible

23 Typical neuroleptics Efficacious Efficacy broadly equivalent 18 / 100 patients benefited from neuroleptic therapy (beyond that with placebo) Haloperidol has a narrow therapeutic window (in dementia) Low-potency antipsychotics (e.g. thioridazine, chlorpromazine) have anticholinergic, sedating and hypotensive properties High-potency antipsychotics (e.g. haloperidol) cause more severe extrapyramidal side-effects Devanand et al (1998); Schneider et al (1990

24 Benzodiazepines in dementia Frequently used, rarely studied Considerable adverse effects falls confusion oversedation disinhibition If absolutely unavoidable, use short term only Short half-life, hepatic metabolism, no active metabolites are favourable qualities (e.g. lorazepam, temazepam) McCarten et al (1995); Sunderland et al (1989)